IL-1 signaling pathway
Interleukin-1 (IL-1) is a proinflammatory cytokine produced by activated macrophages,
endothelial cells, B cells and fibroblasts. IL-1 stimulates a broad spectrum of immune
and inflammatory responses [1], [2].
There are two forms of IL-1 encoded by distinct genes, IL-1 alpha
and IL-1 beta. IL-1 induces cellular response
through its receptor composed of two subunits, Interleukin 1 receptor type I
(IL-1RI) and Interleukin 1 receptor accessory protein
(IL1RAP) [3], [4].
Activated by binding of either of its ligands IL-1 alpha
and IL-1 beta, IL-1RI binds to the adaptor
protein Myeloid differentiation primary response gene 88
(MyD88) that activates Interleukin-1 receptor-associated
kinase 4 (IRAK4) and Interleukin-1 receptor-associated
kinase 1 (IRAK1). The adaptor protein Toll interacting
protein (TOLLIP) forms a complex with
IRAK1 in resting cells and inhibits IL-1-induced signaling
by blocking IRAK1 phosphorylation [5], [6], [7]. IRAK4 phosphorylates and
activates IRAK1. The latter subsequently associates with TNF
receptor-associated factor 6 (TRAF6) causing oligomerization
and activation of TRAF6 that stimulates two distinct
signaling pathways leading to the activation of transcription factors Nuclear factor
kappa-B (NF-kB p50/p65) and Activator protein 1
(AP-1) [1], [7].
TRAF6 is a ubiquitin ligase (E3) that functions with the
ubiquitin conjugating (E2) complex consisting of Ubiquitin-conjugating enzyme E2 variant
1 (UEV1A) and Ubiquitin-conjugating enzyme E2N
(UBC13) to catalyze the synthesis of Lys63-linked
polyubiquitin chains on target proteins including TRAF6
itself. Ubiquitinated TRAF6 then forms a complex with
Mitogen-activated protein kinase kinase kinase 7 interacting proteins 1 and 2
(TAB1 and TAB2) and
Mitogen-activated protein kinase kinase kinase 7 (TAK1).
TAK1 phosphorylates the Inhibitor of kappa light polypeptide
gene enhancer in B-cells kinase beta (IKK-beta), a subunit
of the Inhibitor of kB kinase complex (IKK complex). IKK complex is composed of one
regulatory subunit, Inhibitor of kappa light polypeptide gene enhancer in B-cells kinase
gamma (IKK-gamma), and two catalytic subunits, Conserved
helix-loop-helix ubiquitous kinase (IKK-alpha) and
IKK-beta, forming the IKK complex catalytic core
(IKK (cat)) [8], [9].
TAK1 also phosphorylates and activates Mitogen-activated
protein kinase kinase kinase 14 (NIK) that phosphorylates
IKK-alpha and stimulates its activity
[10].
IKK (cat) then phosphorylates the Inhibitor of NF-kB
(I-kB), leading to its ubiquitylation and subsequent
degradation. This allows NF-kB p50/p65 to translocate into
the nucleus and induce the expression of Interferon regulatory factor 1
(IRF1), Heme oxygenase 1,
Prostaglandin-endoperoxide synthase 2 (COX-2), Nitric oxide
synthase 2A (iNOS), Coagulation factor III
(Tissue factor) and proinflammatory cytokines, such as Tumor
necrosis factor (TNF-alpha), Interleukin 6
(IL-6) and Interleukin 8 (IL-8)
[7], [8], [9], [11], [12], [13], [14], [15], [16], [17].
Another signaling pathway, TRAF6/ ECSIT homolog
(SITPEC)/ Mitogen-activated protein kinase kinase kinase 1
(MEKK1), activates both NF-kB p50/p65
and AP-1 [18].
TAK1 and MEKK1 are
responsible for the phosphorylation and activation of mitogen-activated protein kinase
kinases 3, 4 and 6 (MEK3, MEK4
and MEK6). The three MEKs phosphorylate and activate
Mitogen-activated protein kinases 8-10 (JNK(MAPK8-10)) and
Mitogen-activated protein kinase 14 (p38alpha) leading to
phosphorylation of the AP-1 subunit, Jun oncogene (c-Jun)
and activation of AP-1 transcription factors, including
c-Jun homodimer (c-Jun/c-Jun) [7], [19], [20], [21], [22].
p38alpha also phosphorylates Signal transducer and
activator of transcription 1 (STAT1) which up-regulates
IRF1 expression. STAT1
and IRF1 are involved in iNOS
expression [13], [19].
c-Jun-containing AP-1 complexes induce the expression of Heme oxygenase
1, F3,
Endothelin-1, Plasminogen activator inhibitor-1
(PAI1), Ceruloplasmin and
multiple cytokines, including TNF-alpha,
IL-6 and IL-8. [19], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36].
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